Device and Method for Delivering Micronized Therapeutic Agents in the Body

ABSTRACT

The present invention provides a catheter and catheter assembly for delivering micronized therapeutic agents to a target site in the body and, in particular, to a target site in the heart. The micronized therapeutic agents are delivered in aerosol form or dry powder form. The present invention also provides a method of delivering micronized therapeutic agents to a target site in the body by placing the therapeutic agents in a catheter, positioning the catheter in the target site, and exposing the therapeutic agents to an energizing mechanism sufficient to create supersonic flow to carry the therapeutic agents from a stationary state in the catheter to a mobile state towards the target site.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a continuation of U.S. application Ser. No.10/455298 filed on Jun. 6, 2003, which is incorporated herein byreference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Not Applicable.

FIELD OF THE INVENTION

The present invention relates to the delivery of micronized therapeuticagents to a target site in the body through the use of a catheter andcatheter assembly.

BACKGROUND OF THE INVENTION

Therapeutic agents are often delivered directly to target sites ofdiseased tissue in various contemporary medical procedures. This directdelivery has proven to be an advantageous approach when treatingnumerous medical conditions. Advantages of this procedure are that onlythe target site may be exposed to the therapeutic and a controlled doseof therapeutic may be directly delivered to the target tissue.

Despite the advantages of direct delivery, one pronounced disadvantageis that the low viscosity of the therapeutic may result in thetherapeutic being ejected or squeezed back through its point of entry inthe target tissue. This problem is exacerbated in situations where thetherapeutic is injected into an actively contracting tissue such as themyocardium of the heart. In such a case, the low-viscosity therapeuticmay be ejected or squeezed out through its point of entry by therepeated expansion and contraction of the heart muscle. This unintendedand unwanted leakage can result in an unascertainable dosage of thetherapeutic being ultimately received by the target site and arbitraryand unwanted interaction between leaked therapeutic and neighboringtissue and muscle.

As such, it is advantageous for a therapeutic to have a high solidcontent to retard its ejection from a target site. A therapeutic with ahigh solid to fluid ratio, however, may resist passage through adelivery lumen thereby necessitating the use of a solvent to provide anoperative balance of solids to fluids. In these cases, however, thesolvent employed may be toxic in relation to the target site orincompatible with the therapeutic.

There is, therefore, a need in the art for a method and apparatus thatprovides efficient direct delivery of a therapeutic to a target sitewhile allowing for easy passage through a delivery lumen of a deliverydevice.

SUMMARY OF THE INVENTION

One embodiment of the present invention provides a method of deliveringtherapeutic agents to a target site in the body comprising providing acatheter having a distal end and a proximal end, placing therapeuticagents in the catheter, positioning the distal end of the catheter atthe target site, exposing the therapeutic agents to an energizingmechanism to move the therapeutic agents from a stationary state to amobile state, micronizing the therapeutic agents to form micronizedtherapeutic agents, and ejecting the micronized therapeutic agents fromthe distal end of the catheter to the target site.

Another embodiment of the present invention provides a method ofdelivering therapeutic agents to a target site in the heart comprisingproviding a catheter having a distal end and a proximal end, positioningthe distal end of the catheter at the target site of the heart, anddelivering micronized therapeutic agents through the catheter to thetarget site of the heart.

Another embodiment of the present invention provides a catheter assemblycomprising a catheter having a lumen extending therethrough, a proximalend, and a distal end including a nozzle. The catheter includes atherapeutic agent reservoir, a pressurization chamber located betweenthe therapeutic agent reservoir and the nozzle, a loading valvepositioned between the therapeutic agent reservoir and thepressurization chamber, and an injection valve positioned between thepressurization chamber and the nozzle. The catheter assembly furthercomprises a pressurized gas delivery tube having a first end and asecond end, the first end connected to a pressurized gas source and thesecond end in fluid communication with the pressurization chamber of thecatheter.

Yet another embodiment of the present invention provides a catheterassembly comprising a catheter having a lumen extending therethrough, aproximal end, and a distal end including a nozzle. The catheter includesa therapeutic agent reservoir, a vacuum chamber located between thetherapeutic agent reservoir and the nozzle, and a loading valvepositioned between the therapeutic agent reservoir and the vacuumchamber.

The catheter assembly further includes a vacuum delivery tube having afirst end and a second end, the first end connected to a vacuum sourceand the second end in fluid communication with the vacuum chamber of thecatheter.

Another embodiment of the present invention provides a cathetercomprising a shaft having a lumen extending therethrough and a rotorlocated within the lumen of the shaft, the rotor configured to acceptmicronized therapeutic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an embodiment of a catheter assembly according to thepresent invention.

FIG. 2 depicts an alternative embodiment of a catheter assemblyaccording to the present invention.

FIG. 3 depicts an embodiment of a catheter assembly according to thepresent invention.

FIG. 4 depicts an embodiment of a catheter according to the presentinvention.

FIG. 5 depicts an alternative embodiment of a catheter according to thepresent invention.

FIG. 6 depicts an embodiment of a catheter according to the presentinvention.

FIG. 7 depicts a component of a catheter according to the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is generally directed to a device and method ofdelivering micronized therapeutic agents to a target site of the body bypositioning a catheter at a target site and delivering micronizedtherapeutic agents through the catheter to the target site. Themicronized therapeutic agents are delivered to the target site of thebody by any energizing mechanism sufficient to create a high speed flow,such as a supersonic flow, to carry the micronized therapeutic agentsfrom a stationary state in the catheter to a mobile state. Non-limitingexamples of such energizing mechanisms include pressurized gas, vacuum,mechanical force, electric potential gradient, and centripetal force.

Referring to FIGS. 1 and 2, one embodiment of the present invention,where the energizing mechanism is pressurized gas, provides a catheterassembly 10 comprising a catheter 20 having a lumen 85 extendingtherethrough, a proximal end 30, and a distal end 35 including a nozzle80 having a channel 95 extending therethrough. In this embodiment of thepresent invention, catheter 20 has at least two compartments: atherapeutic agent reservoir 40 and a pressurization chamber 50, thelatter of which is located between therapeutic agent reservoir 40 andnozzle 80. Catheter 20 further includes a loading valve 60 positionedbetween therapeutic agent reservoir 40 and pressurization chamber 50 andan injection valve 70 positioned between pressurization chamber 50 andnozzle 80. Preferably, therapeutic agent reservoir 40, pressurizationchamber 50, loading valve 60, and injection valve 70 are located closerto distal end 35 of catheter 20 than proximal end 30. Catheter assembly10 further comprises a pressurized gas delivery tube 90 having a firstend (not shown) and a second end 91. First end is connected to apressurized gas source (not shown) and second end 91 is in fluidcommunication with pressurization chamber 50 of catheter 20. Deliverytube 90 may be located outside of catheter 20, as illustrated in FIG. 1,or inside lumen 85 of catheter 20, as illustrated in FIG. 2.

In an exemplary use of catheter assembly 10 illustrated in FIG. 1 or 2,therapeutic agents are loaded in the therapeutic agent reservoir 40,catheter 20 is inserted into the body, and nozzle 80 is placed in thetarget site. Loading valve 60 is opened and the therapeutic agents intherapeutic agent reservoir 40 are introduced into pressurizationchamber 50. Loading valve 60 is then closed and pressurized gas isdelivered to pressurization chamber 50 via delivery tube 90. Once asufficient amount of pressure accumulates in pressurization chamber 50,injection valve 70 is opened and the therapeutic agents pass throughnozzle 80 and enter the target site.

Although the pressurized gas that is used to create the high pressure inpressurization chamber 50 varies, it is preferably maintained at apressure of about 1000 pounds per square inches. (PSI). Preferably, thegas is helium, because of its light weight and characteristic of havinga high speed of expansion. Other preferred gases include nitrogen, air,or hydrogen.

The therapeutic agents may be micronized prior to loading in therapeuticagent reservoir 40 or may be micronized prior to exit from catheter 20.For example, the therapeutic agents loaded in catheter 20 may have areduced particle size such as a micronic particle size or thetherapeutic agents may have any particle size and are atomized by anarrow channel 95 of nozzle 80 prior to exit from catheter 20.

In an alternative embodiment, therapeutic agent reservoir 40 andpressurization chamber 50 are not compartments of catheter 20, but arecomponents that are inserted into catheter 20. For example,pressurization chamber 50 could comprise a micro-cylinder filled withgas at a specific pressure and having a gas cylinder tip, andtherapeutic agent reservoir 40 could comprise a cassette or packagefilled with a predetermined amount of micronized therapeutic agents. Tooperate this device according to the present invention, the catheter ispositioned at the target site and an actuation pin contacts and breaksthe gas cylinder tip of the micro-cylinder. Breaking of the gas cylindertip releases the compressed gas inside the micro-cylinder, which burststhe drug cassette or package and delivers the therapeutic agent to thetarget site.

Catheter assembly 10 may also include a gauge to measure the pressure inthe pressurization chamber 50 to determine when a threshold pressure hasbeen obtained and therefore to determine when to terminate delivery ofthe pressurized gas from the pressurized gas source.

Referring to FIG. 3, another embodiment of the present invention, wherethe energizing mechanism is a vacuum source, provides a catheterassembly 15 comprising a catheter 20 having a lumen 85 extendingtherethrough, a proximal end 30, and a distal end 35 including a nozzle80 having a channel 95 extending therethrough. In this embodiment of thepresent invention, catheter 20 also has at least two compartments: atherapeutic agent reservoir 40 and a vacuum chamber 55, the latter ofwhich is located between therapeutic agent reservoir 40 and nozzle 80.Catheter 20 further includes a loading valve 60 positioned betweentherapeutic agent reservoir 40 and vacuum chamber 55. Preferably,therapeutic agent reservoir 40, vacuum chamber 55 and loading valve 60are located closer to distal end 35 of catheter 20 than proximal end 30.Catheter assembly 10 further comprises a vacuum delivery tube 96 havinga first end 101 and a second end 102 wherein first end 101 is connectedto a vacuum source 97 and second end 102 is in fluid communication withvacuum chamber 55. Delivery tube 96 may be located outside of catheter20, as illustrated in FIG. 3, or inside lumen 85 of catheter 20.

In an exemplary use of this embodiment, therapeutic agents are loaded incatheter 20, catheter 20 is inserted into the body, and nozzle 80 ispressed against the target site to create a sealed environment betweencatheter 20 and the target site. Vacuum source 97 is activated and avacuum is drawn through vacuum delivery tube 96 into vacuum chamber 55to reduce the pressure inside vacuum chamber in relation to the pressurein therapeutic agent reservoir 40. Loading valve 60 is then opened andtherapeutic agents are drawn into vacuum chamber 55 and pass throughchannel 95 of nozzle 80 into the target site. Once again, thetherapeutic agents may be micronized prior to loading into catheter 20or may be micronized prior to exit from catheter 20. For example, thetherapeutic agents loaded in catheter 20 may have a reduced particlesize or the therapeutic agents may have any particle size and areatomized by a narrow channel 95 of nozzle 80 prior to exit from catheter20. Although the embodiment depicted in FIG. 3, illustrates a vacuumsource 97 being used as the energizing mechanism to move the micronizedtherapeutic agent from a stationary state to a mobile state, a vacuumsource may also be used in conjunction with other energizing mechanismsdescribed herein or contemplated by the present invention to maximizethe speed of the energizing mechanism, minimize the frictionaldeacceleration of the micronized therapeutic agents and/or to reduce theair pressure inside catheter 20.

Referring to FIGS. 4 and 5, another embodiment of the present invention,where the energizing mechanism is centripetal force, provides a catheter20 comprising a shaft 110 having a lumen 85 extending therethrough and arotor 100 located within lumen 85. Rotor 100 is configured to acceptmicronized therapeutic agents 130. As illustrated in FIG. 4, rotor 100may be in the form of a cylinder which can hold micronized therapeuticagents 130, or as illustrated in FIG. 5, rotor 100 may be in the form ofa disk to which micronized therapeutic agents 130 can adhere. Othersuitable configurations of rotor 100 will be readily appreciated by oneskilled in the art and therefore such other configurations are withinthe scope of the present invention. In order to release micronizedtherapeutic agents 130 from rotor 100 to the target site, rotor 100 isrotated at a high speed as indicated by arrow a and then the rotation isterminated causing micronized therapeutic agents 130 to eject from therotor 100 in a direction tangential to the axis of the rotor's rotationas indicated by arrow A. The velocity of the micronized therapeuticagents 130 is controlled by the circular velocity of rotor 100.

Referring specifically to FIG. 5, in embodiments where rotor 100 is adisk, and micronized therapeutic agents 130 are bound to the outer edgeof rotor 100, the micronized therapeutic agents may be control releasedby focusing an energy beam 140, such as a laser beam, at a specificpoint on the outer edge of rotor 100. The energy of the beam 140 isadapted to and causes release of the micronized therapeutic agents 130from the surface of the rotor 100, causing such micronized therapeuticagents to continue at a predetermined velocity in a straight linetangential to the point of release and thus to be directed towards thetarget site. The micronized therapeutic agents 130 may be attached torotor 100, for example, by electrostatic forces, by their natural stickynature, or by the evaporation of ethanol or another solvent in which themicronized therapeutic agents have been suspended. The energy beam isselected to impart energy of a nature and in an amount sufficient toovercome the forces of adhesion existing between the micronizedtherapeutic agents 130 and the rotor and to release the micronizedtherapeutic agents 130 without adversely affecting the micronizedtherapeutic agents essential properties.

Referring to FIG. 6, another embodiment of the present invention, wherethe energizing mechanism is a mechanical mechanism, provides a catheter20 having a lumen 85 extending therethrough, and having a distal end 35including a needle 160 having a channel 170 extending therethrough. Amechanical member, such as a plunger 150, is located within lumen 185and is configured to exert pressure on therapeutic agents located withinlumen 85 to eject the therapeutic agents in micronized form throughchannel 170 of needle 160 into the target site. Although the mechanicalmember is depicted as a plunger in FIG. 5, any other mechanical membercapable of exerting pressure on the therapeutic agents is also withinthe scope of the present invention. The therapeutic agents may bemicronized prior to loading in catheter 20 or may be micronized prior toexit from catheter 20. For example, the therapeutic agents loaded incatheter 20 may have a reduced particle size or the therapeutic agentsmay have any particle size and are atomized by a narrow channel 170 ofneedle 160 prior to exit from catheter 20.

Another embodiment of the present invention, where the energizingmechanism is an electric potential gradient, provides a catheterassembly comprising a catheter having a lumen extending therethrough, aproximal end including an active electrode, and a distal end including acounter electrode and a nozzle. The catheter assembly also includes asource of electrical energy such as a battery or pulse generator towhich the active electrode and counter electrode are connected. Acharged therapeutic agent is delivered through the active electrode andmigrates along the electric potential gradient formed by the circuit ofthe counter electrode and the active electrode through the nozzle of thecatheter to the target site. For example, if the therapeutic agent to bedelivered is positively charged, then an anode will be the activeelectrode and a cathode will be the counter electrode to complete theelectrical circuit. If the therapeutic agent to be delivered isnegatively charged, then a cathode will serve as the active electrodeand an anode will be the counter electrode.

With respect to particular details of the present invention, inembodiments including an injection valve 70 and/or a loading valve 60,these valves may be any type of valve such as, for example, a plugvalve, a ball valve, a butterfly valve, or a gate valve. Preferably,injection valve 70 comprises a valve stem 200 a, 200 b as illustrated inFIG. 7 that is actuated by exertion of force thereupon. In particular,injection valve 70 includes a valve stem 200 a, 200 b, which is a hollowmember, an axially elongated pin 210 a, 210 b, and a seal 220 a, 220 bthat covers valve stem 200 a, 200 b. Although FIG. 7 depicts two valvestems 200 a, 200 b, only at least one valve stem is contemplated by thispreferred embodiment of the present invention. As illustrated in FIG.7A, seals 220 cover respective valve stems 200 a, 200 b in a restingposition thereof (i.e. when no force is exerted upon valve stems 200 a,200 b) so that no therapeutic agents are released from pressurizationchamber 50 into channel 95 of nozzle 80. As illustrated in FIG. 7B, inan actuated position of valve stems 200 a, 200 b, when force is exertedon valve stem 200 a, pin 210 a depresses pin 210 b such that valve stems200 a, 200 b are released from contact with their respective seals 220a, 220 b and the aerosol of therapeutic agents are released frompressurization chamber 50 and pass around pins 210 a and 210 b, throughvalve stems 200 a, 200 b and into nozzle 80 as indicated by arrows A.The force exerted on valve stem 200 a can originate, for example, from apre-set amount of pressure released from a pressurization source throughpressurized gas delivery tube 90 into pressurization chamber 50, asdescribed in relation to FIGS. 1 and 2 or by a pre-set amount ofpressure created by vacuum source 97 through vacuum delivery tube 96into vacuum chamber 55 as described in relation to FIG. 3, or bymechanical force created by a mechanical member as described in relationto FIG. 6.

With respect to characteristics of the micronized therapeutic agentsaccording to the present invention, the therapeutic agents may bemicronized prior to entry into a catheter according to the presentinvention or may be micronized prior to exit from the catheter. Withrespect to being micronized prior to entry into a catheter, thetherapeutic agents may be micronized by any means known in the art suchas micronization or microencapsulation by destructive or constructivemethods. Non-limiting examples of destructive methods include crushingand grinding, granulation, and spray formation. Non-limiting examples ofconstructive methods include evaporation/condensation, physico-chemicalmethods, crystallization, and vapor condensation. The micronizedtherapeutic agents are delivered to the target site at a high velocityin either solid dry powder form or aerosol form. Preferably themicronized therapeutic agents are delivered at velocities of at leastabout 150 m/s or more, and more preferably at velocities of about250-300 m/s or greater.

With respect to micronizing the therapeutic agents prior to exit from acatheter according to the present invention, the catheter may define orinclude a baffle 4 or narrow passage near the distal end thereof toatomize the therapeutic agents prior to exit from the catheter.

Notwithstanding how the therapeutic agents are micronized, thetherapeutic agents may be directly inserted into a catheter (or,specifically, a therapeutic agent reservoir) according to the presentinvention or may be inserted into a cassette or cylinder which is, inturn, inserted into a catheter. In the latter embodiment, the cassette 2or cylinder would burst or rupture upon the application of theenergizing mechanism to the cassette or cylinder thereby releasing thetherapeutic agent to the target site.

With respect to the micronized “therapeutic agent” such an agent may beone or more “therapeutic agents” or “drugs.” The terms “therapeuticagents” and “drugs” are used interchangeably herein and includepharmaceutically active compounds, nucleic acids with and withoutcarrier vectors such as lipids, compacting agents (such as histones),virus (such as adenovirus, adenoassociated virus, retrovirus, lentivirusand .alpha.-virus), polymers, hyaluronic acid, proteins, cells and thelike, with or without targeting sequences.

Specific examples of therapeutic agents used in conjunction with thepresent invention include, for example, pharmaceutically activecompounds, proteins, cells, oligonucleotides, ribozymes, anti-senseoligonucleotides, DNA compacting agents, gene/vector systems (i.e., anyvehicle that allows for the uptake and expression of nucleic acids),nucleic acids (including, for example, recombinant nucleic acids; nakedDNA, cDNA, RNA; genomic DNA, cDNA or RNA in a non-infectious vector orin a viral vector and which further may have attached peptide targetingsequences; antisense nucleic acid (RNA or DNA); and DNA chimeras whichinclude gene sequences and encoding for ferry proteins such as membranetranslocating sequences (“MTS”) and herpes simplex virus-1 (“VP22”)),and viral liposomes and cationic and anionic polymers and neutralpolymers that are selected from a number of types depending on thedesired application. Non-limiting examples of virus vectors or vectorsderived from viral sources include adenoviral vectors, herpes simplexvectors, papilloma vectors, adeno-associated vectors, retroviralvectors, and the like. Non-limiting examples of biologically activesolutes include anti-thrombogenic agents such as heparin, heparinderivatives, urokinase, and PPACK (dextrophenylalanine proline argininechloromethylketone); anti-restenosis agents such as cladribine;antioxidants such as probucol and retinoic acid; angiogenic andanti-angiogenic agents and factors; anti-proliferative agents such asenoxaprin, angiopeptin, rapamycin, angiopeptin, monoclonal antibodiescapable of blocking smooth muscle cell proliferation, hirudin, andacetylsalicylic acid; anti-inflammatory agents such as dexamethasone,prednisolone, corticosterone, budesonide, estrogen, sulfasalazine,acetylsalicylic acid, and mesalamine; calcium entry blockers such asverapamil, diltiazem and nifedipine;antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel,5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine,cisplatin, vinblastine, vincristine, epothilones, endostatin,angiostatin and thymidine kinase inhibitors; antimicrobials such astriclosan, cephalosporins, aminoglycosides, and nitrofurantoin;anesthetic agents such as lidocaine, bupivacaine, and ropivacaine;nitric oxide (NO) donors such as linsidomine, molsidomine, L-arginine,NO-protein adducts, NO-carbohydrate adducts, polymeric or oligomeric NOadducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, anRGD peptide-containing compound, heparin, antithrombin compounds,platelet receptor antagonists, anti-thrombin antibodies, anti-plateletreceptor antibodies, enoxaparin, hirudin, Warafin sodium, Dicumarol,aspirin, prostaglandin inhibitors, platelet inhibitors and tickantiplatelet factors; vascular cell growth promotors such as growthfactors, growth factor receptor antagonists, transcriptional activators,and translational promotors; vascular cell growth inhibitors such asgrowth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogenous vascoactive mechanisms; survival geneswhich protect against cell death, such as anti-apoptotic Bcl-2 familyfactors and Akt kinase; and combinations thereof Cells can be of humanorigin (autologous or allogenic) or from an animal source (xenogeneic),genetically engineered if desired to deliver proteins of interest at theinsertion site and any modifications to such cells are routinely made byone skilled in the art.

Polynucleotide sequences useful in practice of the invention include DNAor

RNA sequences having a therapeutic effect after being taken up by acell. Examples of therapeutic polynucleotides include anti-sense DNA andRNA; DNA coding for an anti-sense RNA; or DNA coding for tRNA or rRNA toreplace defective or deficient endogenous molecules. The polynucleotidescan also code for therapeutic proteins or polypeptides. A polypeptide isunderstood to be any translation product of a polynucleotide regardlessof size, and whether glycosylated or not. Therapeutic proteins andpolypeptides include as a primary example, those proteins orpolypeptides that can compensate for defective or deficient species inan animal, or those that act through toxic effects to limit or removeharmful cells from the body. In addition, the polypeptides or proteinsthat can be injected, or whose DNA can be incorporated, include withoutlimitation, angiogenic factors and other molecules competent to induceangiogenesis, including acidic and basic fibroblast growth factors,vascular endothelial growth factor, hif-1, epidermal growth factor,transforming growth factor alpha and beta, platelet-derived endothelialgrowth factor, platelet-derived growth factor, tumor necrosis factoralpha, hepatocyte growth factor and insulin like growth factor; growthfactors; cell cycle inhibitors including CDK inhibitors;

anti-restenosis agents, including p15, p16, p18, p19, p21, p2′7, p53,p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) and combinationsthereof and other agents useful for interfering with cell proliferation,including agents for treating malignancies; and combinations thereof.Still other useful factors, which can be provided as polypeptides or asDNA encoding these polypeptides, include monocyte chemoattractantprotein (“MCP-1”), and the family of bone morphogenic proteins(“BMP's”). The known proteins include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6(Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13,BMP-14, BMP-15, and BMP-16. Currently preferred BMP's are any of BMP-2,BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can beprovided as homodimers, heterodimers, or combinations thereof, alone ortogether with other molecules. Alternatively or, in addition, moleculescapable of inducing an upstream or downstream effect of a BMP can beprovided. Such molecules include any of the “hedgehog” proteins, or theDNA's encoding them.

To provide controlled release of the therapeutic agents used in thepresent invention, the therapeutic agents may be microencapsulated withpolymers to form a polymeric material/therapeutic agent matrix.Preferably, the polymer is characterized by all of the following:biocompatibility, controlled release characteristics, biodegradationcapabilities, transfection capabilities, deterrence to the flocculationof the therapeutic agents, and sufficient density if utilized in aerosolform. Such a polymeric material/therapeutic agent matrix can be formedby admixing a therapeutic agent with a liquid polymer, in the absence ofa solvent, to form a liquid polymer/therapeutic agent mixture. Curing ofthe mixture typically occurs in situ. To facilitate curing, across-linking or curing agent may be added to the mixture prior toapplication thereof. Addition of the cross-linking or curing agent tothe polymer/therapeutic agent liquid mixture should not occur too far inadvance of the application of the mixture in order to avoid over-curingof the mixture prior to application thereof. Curing may also occur insitu by exposing the polymer/therapeutic agent mixture, afterapplication to the luminal surface, to radiation such as ultravioletradiation or laser light, heat, or by contact with metabolic fluids suchas water at the site where the mixture has been applied to the luminalsurface. In coating systems employed in conjunction with the presentinvention, the polymeric material may be either bioabsorbable orbiostable. Any of the polymers described herein that may be formulatedas a liquid may be used to form the polymer/therapeutic agent mixture.When delivered into the target site, the therapeutic agent is releasedfrom the polymer as it slowly dissolves into the aqueous bodily fluidsand diffuses out of the polymer.

The polymer used in the present invention to encapsulate the therapeuticagent is preferably capable of absorbing a substantial amount of drugsolution and may be hydrophilic or hydrophobic, and may be selected fromthe group consisting of polycarboxylic acids, cellulosic polymers,including cellulose acetate and cellulose nitrate, gelatin,polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyanhydridesincluding maleic anhydride polymers, polyamides, polyvinyl alcohols,copolymers of vinyl monomers such as EVA, polyvinyl ethers, polyvinylaromatics, polyethylene oxides, glycosaminoglycans, polysaccharides,polyesters including polyethylene terephthalate, polyacrylamides,polyethers, polyether sulfone, polycarbonate, polyalkylenes includingpolypropylene, polyethylene and high molecular weight polyethylene,halogenated polyalkylenes including polytetrafluoroethylene,polyurethanes, polyorthoesters, proteins, polypeptides, silicones,siloxane polymers, polylactic acid, polyglycolic acid, polycaprolactone,polyhydroxybutyrate valerate and blends and copolymers thereof as wellas other biodegradable, bioabsorbable and biostable polymers andcopolymers. Encapsulation from polymer dispersions such as polyurethanedispersions (BAYHDROL®, etc.) and acrylic latex dispersions are alsowithin the scope of the present invention. The polymer may be a proteinpolymer, fibrin, collagen and derivatives thereof, polysaccharides suchas celluloses, starches, dextrans, alginates and derivatives of thesepolysaccharides, an extracellular matrix component, hyaluronic acid, oranother biologic agent or a suitable mixture of any of these, forexample. In one embodiment of the invention, the preferred polymer ispolyacrylic acid, available as HYDROPLUS® (Boston ScientificCorporation, Natick, Mass.), and described in U.S. Pat. No. 5,091,205,the disclosure of which is hereby incorporated herein by reference.

The methods and devices of the present invention may be implanted orotherwise utilized in any body lumina and organ such as the coronaryvasculature, esophagus, trachea, colon, biliary tract, urinary tract,prostrate, brain, lung, liver, heart, skeletal muscle, kidney, bladder,intestines, stomach, pancreas, ovary, cartilage, eye, bone, and thelike.

The micronized therapeutic agents can be used, for example, in anyapplication for treating, preventing, or otherwise affecting the courseof a disease or tissue or organ dysfunction. For example, the methodsand devices of the present invention can by used to induce or inhibitangiogenesis, as desired, to present or treat restenosis, to treat acardiomyopathy or other dysfunction of the heart, for treatingParkinson's disease or a stroke or other dysfunction of the brain, fortreating cystic fibrosis or other dysfunction of the lung, for treatingor inhibiting malignant cell proliferation, for treating any malignancy,and for inducing nerve, blood vessel or tissue regeneration in aparticular tissue or organ.

The foregoing description has been set forth merely to illustrate theinvention is not intended as being limiting. Each of the disclosedembodiments may be considered individually or in combination with otherembodiments of the invention, other variations, and other aspects of theinvention. Modifications of the disclosed embodiments incorporating thespirit and substance of the invention may occur to persons skilled inthe art. Therefore, the present invention should be construed to includeeverything within the scope of the appended claims and equivalentsthereof.

1. A catheter assembly comprising: a catheter having a lumen extendingtherethrough, a proximal end, and a distal end including a nozzle, thecatheter including: a therapeutic agent reservoir; a pressurizationchamber located between the therapeutic agent reservoir and the nozzle;a loading valve positioned between the therapeutic agent reservoir andthe pressurization chamber; an injection valve positioned between thepressurization chamber and the nozzle; and a pressurized gas deliverytube having a first end and a second end, the first end connected to apressurized gas source and the second end in fluid communication withthe pressurization chamber of the catheter.
 2. The catheter of claim 1,wherein the therapeutic agent reservoir is a cassette filled withtherapeutic agents.
 3. The catheter of claim 1, wherein thepressurization chamber is a micro-cylinder filled with pressurized gas.4. The catheter assembly of claim 1, wherein the pressurized gasdelivery tube is located in the lumen of the catheter.
 5. The catheterassembly of claim 1, wherein the injection valve and the loading valvecomprise valve stems.
 6. The catheter assembly of claim 5, wherein theinjection valve and loading valve further comprise a hollow member, anaxially elongated pin, and a seal, the seal covering the valve stem. 7.The catheter assembly of claim 1 further comprising a pressurized gas,the pressurized gas consisting of: helium, nitrogen, air, and hydrogen.8. The catheter assembly of claim 1 further comprising a pressure gauge,the pressure gauge configured to measure the in the pressurizationchamber.
 9. The catheter assembly of claim 1 further comprising at leastone therapeutic agent disposed within the therapeutic agent reservoir.10. The catheter assembly of claim 9, wherein the therapeutic agentconsists of one or more: pharmaceutically active compounds, nucleicacids, compacting agents, viruses, polymers, hyaluronic acid, proteins,and cells.
 11. The catheter assembly of claim 9, wherein the therapeuticagent is microencapsulated with polymeric material to form a polymericmaterial/therapeutic agent matrix.
 12. A catheter assembly fordelivering micronized therapeutic agents to the heart, the catheterassembly comprising: a catheter having a nozzle at the distal endthereof, the catheter comprising: a therapeutic agent reservoircontaining a therapeutic agent; a pressurization chamber located betweenthe therapeutic agent reservoir and the nozzle, the pressurizationchamber comprising a micro-cylinder filled with a gas; a loading valvepositioned between the therapeutic agent reservoir and thepressurization chamber; and an injection valve positioned between thepressurization chamber and the nozzle.